{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:23:04Z","timestamp":1791296584423,"version":"4.1.0"},"reference-count":26,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,10,25]]},"abstract":"<jats:p>The biological antagonism between Notch and Numb controls the proliferative\/differentiative balance in development and homeostasis. Although altered Notch signaling has been linked to human diseases, including cancer, evidence for a substantial involvement of Notch in human tumors has remained elusive. Here, we show that Numb-mediated control on Notch signaling is lost in \u223c50% of human mammary carcinomas, due to specific Numb ubiquitination and proteasomal degradation. Mechanistically, Numb operates as an oncosuppressor, as its ectopic expression in Numb-negative, but not in Numb-positive, tumor cells inhibits proliferation. Increased Notch signaling is observed in Numb-negative tumors, but reverts to basal levels after enforced expression of Numb. Conversely, Numb silencing increases Notch signaling in normal breast cells and in Numb-positive breast tumors. Finally, growth suppression of Numb-negative, but not Numb-positive, breast tumors can be achieved by pharmacological inhibition of Notch. Thus, the Numb\/Notch biological antagonism is relevant to the homeostasis of the normal mammary parenchyma and its subversion contributes to human mammary carcinogenesis.<\/jats:p>","DOI":"10.1083\/jcb.200406140","type":"journal-article","created":{"date-parts":[[2004,10,19]],"date-time":"2004-10-19T00:14:59Z","timestamp":1098144899000},"page":"215-221","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":390,"title":["Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis"],"prefix":"10.1083","volume":"167","author":[{"given":"Salvatore","family":"Pece","sequence":"first","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"},{"name":"2Dipartimento di Medicina, Chirurgia ed Odontoiatria, Universita\u0300 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Serresi","sequence":"additional","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Santolini","sequence":"additional","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Capra","sequence":"additional","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"},{"name":"3Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, 20139 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Hulleman","sequence":"additional","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Galimberti","sequence":"additional","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Zurrida","sequence":"additional","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Maisonneuve","sequence":"additional","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Viale","sequence":"additional","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"},{"name":"2Dipartimento di Medicina, Chirurgia ed Odontoiatria, Universita\u0300 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Paolo","family":"Di Fiore","sequence":"additional","affiliation":[{"name":"1Istituto Europeo di Oncologia, 20141 Milan, Italy"},{"name":"2Dipartimento di Medicina, Chirurgia ed Odontoiatria, Universita\u0300 degli Studi di Milano, 20122 Milan, Italy"},{"name":"3Istituto Fondazione Italiana per la Ricerca sul Cancro di Oncologia Molecolare, 20139 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2004,10,18]]},"reference":[{"key":"2023072218380612700_BIB1","first-page":"2615","volume":"59","year":"1999","journal-title":"Cancer Res."},{"key":"2023072218380612700_BIB2","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1126\/science.284.5415.770","volume":"284","year":"1999","journal-title":"Science."},{"key":"2023072218380612700_BIB3","doi-asserted-by":"crossref","first-page":"6265","DOI":"10.1128\/MCB.17.11.6265","volume":"17","year":"1997","journal-title":"Mol. 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